DESC:Field of the Invention
The present invention relates generally to the field of process chemistry, and more particularly to a process for the preparation of umeclidinium bromide.

Background of the Invention
4-hydroxy (diphenyl) methyl]-1-(2-[phenylmethyl) oxy] ethyl}-1-azoniabicyclo [2.2.2] octane bromide, generically known as Umeclidinium bromide of formula (I)

is disclosed in the Indian Patent No. 255064, and a process for the preparation of this compound is categorically been taught in Example 84.

Indian Patent No. 311486 discloses an alternative preparation of umeclidinium bromide by reacting (2-bromoethoxy) methyl) benzene with diphenyl (quinuclidine-4-yl) methanol in a dipolar aprotic solvent with a boiling point greater than 80°C.

Indian Published Application No. 201741008151 discloses steps of reacting mixture of 4-bromoquinuclidine and benzophenone with ((2-bromoethoxy) methyl) benzene to obtain umeclidinium.

Chinese Published Application No. 106810546 discloses to synthesis umeclidinium by reacting 1-azabicyclo [2.2.2]oct-4-yl(diphenyl)methanol and (2-bromo-ethoxyyl) methylbenzene.
There exists a need for an alternative process for the preparation of umeclidinium bromide, which offers advantages over those reported in the art.

Summary of the Invention
The present invention provides a process for the preparation of umeclidinium bromide.

In one aspect of the present invention, there is provided a process for the preparation of a compound of formula (II),

In other aspect of the present invention, there is provided a process for the preparation of umeclidinium bromide from a compound of formula (II).

These and other aspects of the present invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein.

Detailed Description of the Invention
The present invention provides a process for the preparation of umeclidinium bromide.

In an embodiment, the present invention provides a process for the preparation of compound of Formula II, which comprises:
(a) converting compound of formula (VI) to compound of formula (V) in a suitable solvent in the presence of suitable dehydrating agent;

Formula (VI) Formula (V)
(b) reacting compound of formula (V) with 1-bromo-2-chloro ethane or suitable acylating agent in a suitable solvent to obtain compound of formula (IV), wherein R1 is -(CH2)2Br or acyl;

Formula (V) Formula (IV)
(c) oxidizing compound of formula (IV) with suitable oxidizing agent in a suitable solvent to obtain compound of formula (III);

Formula (IV) Formula (III)

(d) converting compound of formula (III) to compound of formula (II);

` Formula (III) Formula (II)
(e) coupling of 1-azabicyclo[[2.2.2]oct-4-yl (diphenyl) methanol of formula (II) with ((2-bromoethoxy) methyl) benzene in a suitable solvent form Umeclidinium bromide of formula (I);

Formula (II) Formula (I)

The solvent used in step (a) is selected preferably from ethyl acetate, pyridine, acetonitrile, 1,4-dioxan, chlorinated solvents, preferably methylene dichloride, ethereal solvents, preferably diethyl ether, tetrahydrofuran.

The dehydrating agent used in step (a) is selected preferably from bronsted acid such as sulfuric acid, phosphoric acid, hydrogen bromide, hydrogen iodide, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; anhydrides such as acetic anhydride, trifluoroacetic anhydride, trifluoroacetic anhydride, trifluoromethane sulfonic anhydride; acid chlorides such as methane sulfonyl chloride, p-toluene sulfonylchloride; chlorides such as Thionyl chloride, phosphorous oxy chloride, phosphorous pentachloride, phosphorous trichloride, phosphorous pentoxide; lewis acids such as boron trifluoride.etherate, Aluminium trichloride and Ferric chloride.

The reaction of stage (a) is carried out at 25-100°C.

The acylating agent used in stage (b) is selected preferably from acetic anhydride and acetyl chloride.

The solvent used in the step (b) is selected preferably from ketonic solvents such as acetone; ethereal solvents such as tetrahydrofuran, diethylether, di-isopropylether; and aromatic hydrocarbon such as benzene, toluene, xylene; polar aprotic solvents such as dimethyl formamide, acetonitrile and 1,4-dioxane; chlorinated solvents such as methylene dichloride, chloroform, and carbon tetrachloride.

The base used in stage (b) is selected from inorganic base and organic bases.

The inorganic base used in stage (b) is selected preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as Sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate; Lithium di-isopropylamide and lithium hexamethyl disilazide.

The organic base used in stage (b) is selected preferably from 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 4-Dimethyl aminopyridine (DMAP), Pyridine.

Stage (b) is carried out at the temperature ranging from room temperature to 140°C.

Oxidation in stage (c) is carried out in presence of an anhydrous base selected preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as Sodium carbonate, potassium carbonate, cesium carbonate.

The oxidizing agent used in stage (c) is selected preferably from hydrogen peroxide, peracetic acid, perbenzoic acid,m-cloroperbenzoic acid, dimethyldioxirane, cumene hydroper-oxide, tert-butyl hydroperoxide, urea-H2O2 adduct and oxone.

The solvent used in step (c) is selected preferably from aromatic hydrocarbon such as toluene and xylene; chlorinated solvents such as Methylene dichloride, chloroform, carbon tetrachloride.

When R1 is -(CH2)2Br, or -(CH2)2Cl stage (d) is carried out in presence of Grignard reagent such as isopropylmagnessium chloride and mixture Mg and EDBr.

The reaction is carried out in a solvent preferably selected from ethereal solvents like tetrahydrofuran, diethylether, diisopropylether and aromatic hydrocarbon solvents such as toluene, benzene, heptane and xylene.

This stage is carried out at a temperature range of RT to 160°C.

In stage (d), when R1 is acyl, compound of formula (IV) is converted to compound of formula (II-A) by heating compound (IV) in presence of suitable base in a suitable solvent.
Formula (III) Formula (II-A) Formula (II)
wherein R1 is acyl

The base used is preferably selected preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as Sodium carbonate, potassium carbonate, cesium carbonate.

The reaction is carried out in an aromatic hydrocarbon solvent such as toluene, benzene, heptane and xylene. The reaction proceeds at temperature range from RT to 150°C.

Compound of formula (II-A) is further reduced to compound of formula (II) using a suitable reducing agent selected preferably from a mixture of BF3 etherate and sodium borohydride, Aluminum chloride and sodium borohydride, Borane-tetrahydrofuran and borane-dimethylsulfide.

The solvent used in stage (e) is selected preferably from aromatic hydrocarbons such as toluene, xylene, benzene, diphenyloxide; ethereal solvent such as tetrahydrofuran, di-isopropyl ether, diethylether; nitrile solvent such as acetonitrile; chlorinated solvent such as Methylene dichloride, chloroform, carbon tetrachloride.

Stage (e) is carried out at temperature from room temperature to 250°C.

In another embodiment the present invention provides a process for preparation of Umeclidinium bromide of formula (I), which comprises:
i) converting compound of formula (X) using a suitable brominating agent in a suitable solvent to form to compound of formula (IX)

Formula (X) Formula (IX)
ii) reacting compound of formula (IX) with benzophenone to form compound of formula (VIII) in a suitable solvent;

Formula (IX) Formula (VIII)
iii) reacting compound of formula (VIII) with methyl chloroacetate in presence of suitable solvent and a suitable base to form compound of formula (VII);

Formula (VIII) Formula (VII)
iv) cyclization of compound of formula (VII) to compound of formula (II-B) in presence of a suitable base in a suitable solvent,

Formula (VII) Formula (II-B)
v) conversion of compound (II-B) to compound (II)

Formula (II-B) Formula (II)
vi) reacting-1-azabicyclo[[2.2.2]oct-4-yl (diphenyl) methanol of formula (II) with ((2-bromoethoxy) methyl) benzene in a suitable solvent form Umeclidinium bromide of formula (I);

Formula (II) Formula (I)

The solvent used Stage (i) of this embodiment is selected preferably from chlorinated solvents such as MDC; Etheral solvents such as tetrahydrofuran, diethyether; polar aprotic solvent such as ethylacetate; hydrocarbone solvent such as toluene and Xylene; ketonic Solvents such as acetone, methyl tertbutyl ether, etc.

The brominating agent used in stage (i) is selected preferably from N-Bromo succinimide, N-Bromoacetamide Dibromoisocyanuric acid,1,3-Dibromohydantoin,N-bromothalimide, N-Bromosacchrin and Liquid Bromine

Stage (i) is carried out at -10 to 40°C.

Reaction of compound of formula (IX) with benzophenone in stage (ii) is carried out in presence of Grignard reagent such as Mg & ethylene dibromide.

Stage (ii) is carried out in a solvent selected preferably from Ethereal solvents such as THF, diethyl ether, Di-isopropylether; aromatic hydrocarbon such as Toluene, Benzene, Heptane, Xylene

The reaction of stage (ii) is carried out at a temperature range of RT to 60°C.

Amide formation in stage (iii) is carried in a suitable base selected preferably from Potassium tert-butoxide, Sodium methoxide, NaOH, KOH.
Stage (iii) is carried out in a solvent preferably selected from Alcoholic solvents such as methanol, ethanol, t-butanol; aromatic hydrocarbons such as Toluene, Benzene, Heptane, Xylene. The reaction proceeds at a temperature range from 0-160°C.

Cyclization in stage (iv) is carried out in a suitable solvent preferably selected from alcoholic solvents such as methanol, ethanol, t-butanol; and aromatic hydrocarbon solvent such toluene, benzene, heptane, xylene.

The base used in stage (iv) is selected from potassium tert-butoxide and sodium methoxide, potassium metal, Sodium metal.

The cyclization in stage (iv) proceeds at a temperature range of 0 to 160°C.

Reduction of compound of formula (II-B) to compound of formula (II) in stage (v), proceeds through imine formation. Compound of formula (II-B) is treated with a suitable hydrazine reagent selected from 100% hydrazine, 85% hydrazine, Tosylhydrazide, p-Toluene sulfonyl hydrazide. The reaction is carried out in presence of a suitable acid such as acetic acid and in a suitable alcoholic solvent such as methanol, ethanol and t-butanol.

In situ imine formed is reduced to compound of formula (II) using a suitable reducing agent selected preferably from potassium tert-butoxide, Sodium tert-butoxide, Sodium methoxide, Sodium ethoxide, potassium hydroxide and sodium hydroxide. The reaction proceeds well in presence of suitable glycol such as ethylene glycol, diethylene glycol.

The reaction in stage (v) is carried out at a temperature range from RT to 200°C.

The solvent used in stage (vi) is selected preferably from aromatic hydrocarbons such as toluene, xylene, benzene, diphenyloxide; ethereal solvent such as tetrahydrofuran, di-isopropyl ether, diethylether; nitrile solvent such as acetonitrile; chlorinated solvent such as Methylene dichloride, chloroform, carbon tetrachloride.

Stage (vi) is carried out at temperature from room temperature to 250°C.

,CLAIMS:1. A process for the preparation of umeclidinium bromide of formula (I), the process comprises the steps of:
(i) converting compound of formula (X) using a suitable brominating agent in a suitable solvent to form a compound of formula (IX);

Formula (X) Formula (IX)

(ii) reacting compound of formula (IX) with benzophenone to form a compound of formula (VIII) in a suitable solvent;

Formula (IX) Formula (VIII)
(iii) reacting compound of formula (VIII) with methyl chloroacetate in presence of a suitable solvent and a suitable base to form compound of formula (VII);

Formula (VIII) Formula (VII)
(iv) cyclization of compound of formula (VII) to a compound of formula (II-B) in a presence of a suitable base in a suitable solvent;

Formula (VII) Formula (II-B)
(v) converting compound (II-B) to a compound of formula (II);

Formula (II-B) Formula (II)
(vi) reacting 1-azabicyclo[[2.2.2]oct-4-yl (diphenyl) methanol of formula (II) with ((2-bromoethoxy) methyl) benzene in a suitable solvent to form umeclidinium bromide of formula (I).

Formula (II) Formula (I)
2. The process as claimed in claim 1, wherein the solvent used in step (i) is selected from the group comprising of chlorinated solvent, ethereal solvent, polar aprotic solvent, and ketonic solvent, and wherein the brominating agent is selected from the group comprising of N-bromo succinimide, N-bromoacetamide, dibromoisocyanuric acid, 1, 3-dibromohydantoin, N-bromothalimide, N-bromosacchrin, and liquid bromine.
3. The process as claimed in claim 1, wherein step (ii) is carried out in the presence of a Grignard reagent, and wherein the solvent used in step (ii) is selected from the group comprising of ethereal solvent, and aromatic hydrocarbon.
4. The process as claimed in claim 1, wherein the base used in step (iii) is selected from the group comprising of potassium tert-butoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide, and wherein the solvent used in step (iv) is selected from the group comprising of alcoholic solvent, and aromatic hydrocarbon.
5. The process as claimed in claim 1, wherein the solvent used in step (iv) is selected from the group comprising of alcoholic solvent, and aromatic hydrocarbon, and wherein the base used in step (iv) is selected from the group comprising of potassium tert-butoxide, sodium methoxide, potassium metal, and sodium metal.
6. The process as claimed in claim 1, wherein the formula (II-B) of step (v) is treated with a suitable hydrazine reagent selected from the group comprising of 100% hydrazine, 85% hydrazine, tosylhydrazide, and p-toluene sulfonyl hydrazide.
7. The process as claimed in claim 1, wherein the solvent used in step (vi) is selected from the group comprising of aromatic hydrocarbon, ethereal solvent, nitrile solvent, and chlorinated solvent.
8. A process for the preparation of umeclidinium bromide of formula (I), the process comprises a step of coupling 1-azabicyclo[[2.2.2]oct-4-yl (diphenyl) methanol of formula (II) with ((2-bromoethoxy) methyl) benzene in a solvent to form umeclidinium bromide.
9. The process as claimed in claim 8, wherein the solvent is selected from the group comprising of aromatic hydrocarbon, ethereal solvent, nitrile solvent, and chlorinated solvent.
10. A process for preparing a compound of formula (II), the process comprises the steps of:
(i) converting compound of formula (VI) to compound of formula (V) in a suitable solvent in the presence of a suitable dehydrating agent,

Formula (VI) Formula (V)
(ii) reacting compound of formula (V) with 1-bromo-2-chloro ethane or suitable acylating agent in a suitable solvent to obtain compound of formula (IV)

Formula (V) Formula (IV)

wherein R1 is -(CH2)2Br or acyl,
(iii) oxidizing compound of formula (IV) with a suitable oxidizing agent in a suitable solvent to obtain a compound of formula (III),

Formula (IV) Formula (III)
(iv) converting compound of formula (III) to compound of formula (II)

` Formula (III) Formula (II)
wherein the solvent used in step (i) is selected from the group consisting of ethyl acetate, pyridine, acetonitrile, 1,4-dioxan, chlorinated solvent, ethereal solvent, polar aprotic solvent, and ketonic solvent,

wherein the brominating agent is selected from the group comprising of N-bromo succinimide, N-bromoacetamide, dibromoisocyanuric acid, 1, 3-dibromohydantoin, N-bromothalimide, N-bromosacchrin, and liquid bromine,

wherein the solvent used in step (ii) is selected from the group comprising of ethereal solvent, and aromatic hydrocarbon,

wherein the oxidizing agent used in step (iii) is selected from the group comprising of hydrogen peroxide, peracetic acid, perbenzoic acid,m-cloroperbenzoic acid, dimethyldioxirane, cumene hydroper-oxide, tert-butyl hydroperoxide, urea-H2O2 adduct and oxone,

wherein the solvent used in step (c) is selected from the group comprising of aromatic hydrocarbon and chlorinated solvent.